Cathepsin K is a lysosomal enzyme with a typical acid pH (5.5) optimum. The importance of this enzyme in intracellular (lysosomal) collagenolytic activity has been demonstrated by the accumulation of endocytosed collagen fibrils in fibroblasts treated with a cathepsin K inhibitor in vitro. However, cathepsin K also plays a significant role in extracellular type I collagenolysis in the phagolysosome-like resorption compartment of active osteoclasts in bone. Inhibition of cathepsin K in vitro and in vivo significantly decreases osteoclastic bone resorption. Pycnodysostosis (PD), a genetic disorder in humans characterised by osteosclerosis and short stature is due to a deficiency in cathepsin K activity. Individuals affected with PD have significantly decreased bone collagen turnover, suggesting that cathepsin K is the principle enzyme responsible for physiological bone matrix turnover.
In pathological conditions such as in post-menopausal osteoporosis (and ovariectomy models in rats) and other metabolic bone disorders like Paget's disease, the excessive bone resorption is also associated with collagen turnover by cathepsin K. Furthermore, increased bone turnover in rheumatoid and osteoarthritis is associated with elevated collagen cleavage by cathepsin K.
In contrast, bone lysis and collagen release in cancer metastasis to bone is thought to be predominantly due to enhanced metallo matrix protein (MMP) activity. Similarly, while increased cathepsin K expression in lysosomes of synovial fibroblasts and chrondrocytes has been observed in arthritis, a direct role in extracellular cartilage matrix degeneration has not been demonstrated. In contrast, MMP-driven articular cartilage collagen breakdown in vitro and in arthritic joints has been well documented. Taken together, these data indicate that cathepsin K plays a central role in type I collagenolysis and bone remodelling in physiological and certain pathological conditions. Therefore, mechanisms to inhibit cathepsin K activity represent excellent targets for the treatment of excessive bone turnover.
Although once thought to reside exclusively in osteoclasts, Cathepsin K expression has been discovered in a significant fraction of human breast cancers, prostate cancer and associated metastases.
Furthermore, activation of human pulmonary fibroblasts in primary cell cultures has been found to lead to an increased activity of Cathepsin K and to increase intracellular collagenolytic activity suggesting that Cathepsin K plays a pivotal role in lung matrix homeostasis under physiological and pathological conditions.